The role of various risk factors in relapse with methamphetamine (METH) dependence remains to be determined. METH poses unique challenges, in that it's highly addictive nature is compounded by cognitive deficits. The studies proposed in this project will study cue and drug induced relapse by using the reinstatement model of drug-seeking behavior in rats. The overarching goal of this project is to integrate findings from the animal model of relapse with the clinical projects in the TRAC that are focused on cue reactivity and cognitive dysfunction in METH-dependent humans. We propose the following specific aims: 1) Demonstrate conditioned-cued and drug-primed reinstatement of METH-seeking. We predict that rats that have undergone chronic METH self-administration will show extinction of responding and reinstatement of METH-seeking behavior in the presence of discrete conditioned cues or after METH injections. Furthermore, prolonged exposure to METH should result in resistance to extinction and a greater degree of drug-seeking at the time of reinstatement. 2) Determine the cognitive deficits that arise from chronic METH. This aim will begin with assessing deficits in novel object recognition in rats with a history of chronic METH self-administration. We predict that these deficits will be more severe in animals with greater drug-seeking. In addition, we predict that pre-existing lesions of the orbitofrontal cortex will exacerbate cognitive deficits and METH-seeking. During the course of the P20, as results in METH dependent human subjects are obtained in projects 2 and 4, we will then apply additional cognitive testing procedures in rats that parallel those used in the human subjects. 3) Attenuate relapse and cognitive dysfunction with novel pharmacotherapies. We will test the possibility that facilitation of NMDA receptor function via glycine site modulation by d-cycloserine will facilitate extinction, reduce reinstatement, and improve cognitive performance. We also predict that the glutamate enhancing agents, N-Acetylcysteine and modafinil, will facilitate extinction and reduce reinstatement in animals after METH self-administration and that these drugs will have co-modulating beneficial effects on cognitive deficits. Studies from this aim will give direction to clinical pharmacotherapy approaches in projects 2 and 4, and provide ideas for site-selective drug delivery in project 1. These studies will provide a comprehensive examination of extinction, relapse, and cognitive deficits after chronic METH. In conjunction with the clinical projects, we will modify our experimental approaches as information is derived from human subjects. In turn, we will provide promising leads for the other TRAC projects in regards to pharmacotherapy (projects 2 and 4) or direct brain site injection (Project 1).